Anthracyclines form one of the largest families of naturally occurring bioactive compounds. Several members of this family have shown to be clinically effective anti-neoplastic agents. These include, for example, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and carminomycin. For instance, these compounds have shown to be useful in bone marrow transplants, stem cell transplantation, treatment of breast carcinoma, acute lymphocytic and non-lymphocytic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and other solid cancerous tumors.
Currently known methods used to prepare 4-demethoxy-4-R-daunorubicin-type anthracyclines (where R=H the anthracycline is known as idarubicin) are based on coupling of the aglycone (synthesized by any of the known methods) and protected and activated daunosamine in the presence of silver triflate (AgOSO2CF3), trimethylsilyltriflate ((CH3)3SiOSO2CF3), or a mercuric oxide—mercuric bromide system (HgO—HgBr2). For example, it is currently known to synthesize aglycone using either anthracenetetrone or isobenzofurane as the starting substance. Unfortunately, these methods of aglycone synthesis are complicated by the creation of optically active centers at carbons C7 and C9.
An alternative method of synthesis of 4-demethoxydaunorubicin (idarubicin) utilizes daunorubicin aglycone which is prepared by the acidic hydrolysis of daunorubicin starting material. In this method, at the same time daunosamine is synthesized, with chemical modification, the daunosamine can be further used for glycosylation of the modified aglycone. Earlier methods involved the substitution of 4-MeO aglycone substituent for hydrogen, NH2, or other chemical groups involved demethylation of daunorubicinone, sulfonation of the resulting 4-demethoxydaunorubicinone and substitution of the 4-ArSO2O radical for a 4-ArCH2NH with further reduction of the benzyl radical leading to formation of 4-NH2− radical. See U.S. Pat. No. 4,085,548 entitled 4-DEMETHOXY-4-AMINO-ANTHRACYCLINES, issued Jan. 15, 1991, to Caruso et al., the disclosure of which is incorporated by reference as if set forth fully herein. Further reductive deamination results in production of 4-demethoxydaunorubicin (idarubicin). See EP Application No. 0328399, published Aug. 16, 1989, the disclosure of which is incorporated by reference as if set forth fully herein.
There also has been described a reductive cross-condensation reaction of 4-demethyl-4-Tf-daunorubicinone on the phosphorous hydride—Pd0 catalyzing complexes. See U.S. Pat. No. 5,587,495. In these reactions, 4-R substituted daunorubicinones are produced wherein R=

Similarly, reductive carbonylation of 4-Tf-daunorubicinone on the same catalysts described above results in 4-COOR substituted daunorubicinones. See U.S. Pat. No. 5,218,130. When formate is utilized as a ligand, substitution of 4-O-Tf radical for hydrogen takes place resulting in formation of 4-demethoxydaunorubicinone. See U.S. Pat. No. 5,103,029.